{"gene":"ASXL2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2015,"finding":"ASXL2 forms a mutually exclusive complex with BAP1 (distinct from the BAP1/ASXL1 complex); ASXL2 uses its ASXM domain to interact with the C-terminal domain (CTD) of BAP1, and this interaction is required for ubiquitin binding and H2A deubiquitination at Lys-119. BAP1 is essential for maintaining ASXL2 (but not ASXL1) protein stability, and cancer-associated loss of BAP1 results in ASXL2 destabilization.","method":"Co-immunoprecipitation, in vitro DUB activity assays, mutagenesis of BAP1 CTD and ASXM domains, cell proliferation and senescence assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, in vitro enzymatic assays, domain mutagenesis, multiple orthogonal methods in a single rigorous study","pmids":["26416890"],"is_preprint":false},{"year":2015,"finding":"Cancer-associated mutations in ASXL2 disrupt BAP1 DUB activity, and BAP1 interaction with ASXL2 regulates cell senescence, implicating the BAP1/ASXL2 axis in tumor suppression.","method":"Mutagenesis of ASXL2 cancer-associated variants, DUB activity assays, cell senescence assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assays plus cellular functional readouts with defined mutations, multiple orthogonal methods","pmids":["26416890"],"is_preprint":false},{"year":2022,"finding":"ASXL2, as a subunit of the BAP1 complex, mediates a direct interaction with MLL3/COMPASS, and ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. PRMT4/CARM1 methylates ASXL2 at R639/R641, blocking its binding to MLL3 and impairing MLL3/COMPASS-dependent gene expression.","method":"Co-immunoprecipitation, ChIP-seq, siRNA knockdown, site-directed mutagenesis, arginine methylation assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct interaction confirmed by Co-IP, PTM writer identified by methylation assay, functional consequence assessed by ChIP-seq and gene expression, multiple orthogonal methods","pmids":["36197977"],"is_preprint":false},{"year":2015,"finding":"ASXL2 interacts with PPARγ and regulates osteoclast formation via a PPARγ/c-Fos-dependent pathway; ASXL2 is also required for RANK ligand- and thiazolidinedione-induced bone resorption independently of PGC-1β, and promotes osteoclast mitochondrial biogenesis in a PGC-1β-dependent but c-Fos-independent manner. ASXL2-/- mice are insulin resistant, lipodystrophic, and severely osteopetrotic due to failed osteoclast differentiation.","method":"Asxl2 knockout mice, osteoclast differentiation assays, bone resorption assays, signaling pathway epistasis experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotypes and multiple pathway epistasis experiments across independent signaling branches","pmids":["26051940"],"is_preprint":false},{"year":2015,"finding":"ASXL2 interacts with ligand-bound ERα and mediates ERα transcriptional activation. ASXL2 forms a complex with histone methylation modifiers LSD1, UTX, and MLL2, which are recruited to E2-responsive gene promoters via ASXL2, regulating methylations at H3K4, H3K9, and H3K27. The PHD finger of ASXL2 preferentially binds dimethylated H3K4, which is required for ERα activation.","method":"Co-immunoprecipitation, ChIP-seq, pulldown assays with PHD finger, siRNA knockdown, xenograft tumor assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, PHD finger binding assay, and in vivo xenograft validation; single lab but multiple orthogonal methods","pmids":["26640146"],"is_preprint":false},{"year":2009,"finding":"Loss of Asxl2 in mice reduces trimethylation of histone H3 lysine 27 (H3K27me3) in the heart, demonstrating that Asxl2 promotes PcG-associated histone modification. Asxl2 mutant mice display both posterior and anterior transformations of the axial skeleton, indicating dual roles in PcG and trxG activity. Asxl2-/- mice develop enlarged hearts with impaired ventricular function.","method":"Gene-trap knockout mouse, histone modification analysis (western blot for H3K27me3), skeletal phenotyping, histological analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with direct histone modification measurement and defined skeletal/cardiac phenotypic readouts; replicated by subsequent cardiac study","pmids":["19270745"],"is_preprint":false},{"year":2012,"finding":"Asxl2 is required for maintenance of ventricular function and for repression of β-MHC in adult mouse hearts. Asxl2 and the histone methyltransferase Ezh2 co-localize to the β-MHC promoter, indicating Asxl2 directly represses β-MHC through Ezh2-mediated chromatin modification. Loss of Asxl2 causes progressive deterioration of ventricular function (~37% reduction in fractional shortening by 10 months).","method":"Asxl2-/- mice echocardiography, ChIP showing Asxl2 and Ezh2 co-occupancy at β-MHC promoter, cardiac gene expression analysis","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cardiac functional phenotype, ChIP showing direct promoter co-occupancy with Ezh2, multiple methods in single lab","pmids":["23046516"],"is_preprint":false},{"year":2011,"finding":"Asxl2 regulates bone mineral density and osteoclastogenesis; knockdown of Asxl2 in bone marrow macrophages impairs their ability to form osteoclasts. Asxl2 knockout mice have reduced BMD.","method":"GWAS/systems genetics in HMDP, Asxl2 knockout mice (BMD phenotyping), siRNA knockdown in bone marrow macrophages with osteoclast differentiation assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO phenotype plus siRNA knockdown in primary cells with defined osteoclastogenesis readout, replicated in subsequent independent study","pmids":["21490954"],"is_preprint":false},{"year":2017,"finding":"ASXL2 is required for normal haematopoietic stem cell self-renewal; Asxl2 loss promotes AML1-ETO-driven leukemogenesis. ASXL2 target genes strongly overlap with those of RUNX1 and AML1-ETO, and ASXL2 loss is associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci.","method":"Asxl2 conditional knockout mice, hematopoietic stem cell transplantation assays, ATAC-seq for chromatin accessibility, gene expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with HSC functional assays, ATAC-seq chromatin analysis, and leukemogenesis model; multiple orthogonal methods","pmids":["28516957"],"is_preprint":false},{"year":2017,"finding":"Deletion of Asxl2 in mice leads to MDS-like disease with expanded long-term HSCs and granulocyte-macrophage progenitors. Asxl2 loss enhances HSC self-renewal (paired daughter cell assays) and alters H3K27ac and H3K4me1/2 at loci critical for HSC self-renewal, differentiation, and apoptosis.","method":"Asxl2 knockout mice, bone marrow transplantation, paired daughter cell assays, histone modification ChIP analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with clonal HSC functional assays and direct histone modification measurements; independent replication of HSC phenotype across two concurrent studies","pmids":["28593990"],"is_preprint":false},{"year":2013,"finding":"ASXL2 activates LXRα transcriptional activity through direct interaction with LXRα in the presence of ligand, while ASXL1 suppresses it; knockdown of ASXL2 decreases lipid accumulation in H4IIE cells. ChIP assays show ligand-dependent recruitment of ASXL2 to ABCA1 promoters.","method":"Transcriptional reporter assays, Co-immunoprecipitation, ChIP assay, siRNA knockdown with lipid accumulation readout","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct interaction by Co-IP, ChIP confirmation of promoter recruitment, functional knockdown, single lab","pmids":["24321552"],"is_preprint":false},{"year":2014,"finding":"ASXL2 directly interacts with the LIM domain-containing protein WTIP; WTIP represses ASXL2-stimulated retinoic acid-dependent transcription, blocking ASXL2's stimulatory effect. Both proteins are expressed in mouse embryonic epicardial cells.","method":"Genetic and biochemical interaction assays, luciferase reporter assays in HeLa cells, co-expression analysis in mouse embryonic epicardium","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct interaction confirmed biochemically and genetically, functional reporter assay, single lab with two orthogonal methods","pmids":["25065743"],"is_preprint":false},{"year":2020,"finding":"Myeloid-specific deletion of Asxl2 confers resistance to diet-induced obesity by protecting energy expenditure and brown adipose tissue metabolism, associated with suppressed macrophage inflammatory cytokine expression and relatively increased catecholamines (due to suppressed catecholamine degradation by macrophages). Nanoparticle-based siRNA suppression of macrophage Asxl2 prevented HFD-induced obesity.","method":"Myeloid-specific Asxl2 conditional KO (LysM-Cre), high-fat diet metabolic phenotyping, nanoparticle siRNA delivery in vivo, energy expenditure measurements, cytokine/catecholamine measurements","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined metabolic phenotype plus orthogonal siRNA rescue experiment and mechanistic measurement of catecholamine pathway","pmids":["32310225"],"is_preprint":false},{"year":2026,"finding":"ASXL2 promotes EZH2 binding to the CEP162 promoter region (3482–3511 bp), maintaining H3K27me3 and repressing CEP162 transcription. Hypoxia-induced downregulation of ASXL2 reduces EZH2 occupancy, increases CEP162 expression, and CEP162 then competes with TUBA3A for TUBB3 binding, depleting ciliary TUBB3 and destabilizing axonemal microtubules, causing spermatid maturation defects.","method":"ASXL2 loss-of-function in spermatogenic cells, ChIP for EZH2/H3K27me3 at CEP162 promoter, protein binding/competition assays (TUBB3/CEP162/TUBA3A), spermatid morphology analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and protein interaction assays establish mechanism, but single lab and single publication with no independent replication","pmids":["41782374"],"is_preprint":false},{"year":2025,"finding":"ASXL2 knockdown in human periodontal ligament stem cells (hPDLSCs) impairs osteogenic differentiation, suppresses H3K4me3 (activating mark), and increases H2AK119ub and H3K27me3 (repressive marks) at osteogenic gene loci, demonstrating that ASXL2 modulates osteogenic competency through histone modification balance.","method":"Lentiviral shRNA knockdown in hPDLSCs, ALP activity assay, Alizarin Red mineralization, western blot for H3K4me3/H2AK119ub/H3K27me3, qPCR for osteogenic markers","journal":"International dental journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — loss-of-function with direct histone modification readouts, but single lab and single publication with no independent replication","pmids":["40680514"],"is_preprint":false}],"current_model":"ASXL2 is an epigenetic scaffold protein that forms a mutually exclusive complex with the deubiquitinase BAP1 (through ASXM domain–CTD interaction), stimulating H2A-K119 deubiquitination; it also bridges BAP1 to the MLL3/COMPASS H3K4 methyltransferase complex (interaction negatively regulated by CARM1-mediated methylation at R639/R641), co-occupies target promoters/enhancers with EZH2 to maintain H3K27me3-dependent gene repression, interacts with nuclear receptors PPARγ, LXRα, and ERα to regulate lipid/glucose metabolism and breast cancer cell proliferation, and is required for normal haematopoietic stem cell self-renewal and osteoclastogenesis, with its loss causing MDS-like disease, osteopetrosis, and cardiac dysfunction in mice."},"narrative":{"mechanistic_narrative":"ASXL2 is an epigenetic scaffold protein that couples histone-modifying machineries to chromatin to control gene expression programs governing hematopoiesis, bone remodeling, cardiac function, and metabolism [PMID:26416890, PMID:19270745, PMID:21490954]. It forms a mutually exclusive complex with the deubiquitinase BAP1, engaging the BAP1 C-terminal domain through its ASXM domain to enable ubiquitin binding and H2A-K119 deubiquitination; BAP1 in turn stabilizes ASXL2 protein, and cancer-associated ASXL2 mutations disrupt BAP1 DUB activity, linking this axis to senescence control and tumor suppression [PMID:26416890]. Within the BAP1 complex, ASXL2 bridges to the MLL3/COMPASS H3K4 methyltransferase to sustain enhancer occupancy and target-gene expression, an interaction blocked by CARM1/PRMT4-mediated methylation of ASXL2 at R639/R641 [PMID:36197977]. ASXL2 also acts as a repressive cofactor, co-occupying target promoters with EZH2 to maintain H3K27me3-dependent silencing of genes such as cardiac β-MHC [PMID:19270745, PMID:23046516], while its PHD finger reads dimethylated H3K4 and recruits LSD1, UTX, and MLL2 to mediate ligand-dependent transcriptional activation by ERα and the nuclear receptors PPARγ and LXRα, integrating epigenetic control of lipid and glucose metabolism [PMID:26051940, PMID:26640146, PMID:24321552]. Functionally, ASXL2 is required for normal hematopoietic stem cell self-renewal, and its loss causes MDS-like disease and promotes AML1-ETO-driven leukemogenesis through altered enhancer accessibility and histone marks [PMID:28516957, PMID:28593990], drives osteoclastogenesis and bone mineral density [PMID:26051940, PMID:21490954], and maintains adult ventricular function [PMID:19270745, PMID:23046516]. Beyond these characterized roles, no further mechanistic detail has been established in the available corpus.","teleology":[{"year":2009,"claim":"Establishing whether ASXL2 functions in chromatin regulation in vivo, this work showed it promotes Polycomb-associated H3K27me3 and governs body-axis patterning and heart development.","evidence":"Gene-trap Asxl2 knockout mice with H3K27me3 western blots, skeletal and cardiac phenotyping","pmids":["19270745"],"confidence":"High","gaps":["Direct molecular partners mediating H3K27me3 changes not identified","Dual PcG/trxG activity not mechanistically resolved"]},{"year":2011,"claim":"Addressing the cellular basis of skeletal phenotypes, ASXL2 was shown to be cell-autonomously required for osteoclast formation and bone mineral density.","evidence":"Systems genetics (HMDP), Asxl2 knockout mice BMD phenotyping, siRNA knockdown in bone marrow macrophages with osteoclast differentiation assays","pmids":["21490954"],"confidence":"High","gaps":["Molecular target genes in osteoclast lineage not defined","Chromatin mechanism in osteoclastogenesis unaddressed"]},{"year":2012,"claim":"To pinpoint how ASXL2 controls cardiac gene expression, this study showed it co-occupies the β-MHC promoter with EZH2 to maintain repression and ventricular function.","evidence":"Asxl2-/- echocardiography and ChIP for Asxl2/Ezh2 co-occupancy at the β-MHC promoter","pmids":["23046516"],"confidence":"High","gaps":["Direct physical interaction between ASXL2 and EZH2 not demonstrated biochemically","Genome-wide co-occupancy not mapped"]},{"year":2013,"claim":"Testing whether ASXL family members differentially regulate nuclear receptors, ASXL2 was found to activate LXRα transcription in a ligand-dependent manner, opposite to ASXL1.","evidence":"Reporter assays, Co-IP, ChIP at ABCA1 promoter, siRNA knockdown with lipid accumulation readout","pmids":["24321552"],"confidence":"Medium","gaps":["Single lab without independent replication","Histone-modifying machinery recruited to LXRα targets not defined"]},{"year":2014,"claim":"Identifying a negative regulator of ASXL2 cofactor activity, WTIP was shown to directly bind ASXL2 and repress its retinoic-acid-dependent transcriptional stimulation.","evidence":"Biochemical/genetic interaction assays and luciferase reporters in HeLa cells, epicardial co-expression","pmids":["25065743"],"confidence":"Medium","gaps":["Single lab without independent replication","Physiological context of WTIP-ASXL2 regulation in vivo unresolved"]},{"year":2015,"claim":"Defining the core biochemical complex, ASXL2 was shown to form a BAP1-specific (mutually exclusive with ASXL1) complex via ASXM–CTD contact required for H2A-K119 deubiquitination, with BAP1 reciprocally stabilizing ASXL2 and cancer mutations disrupting DUB activity.","evidence":"Reciprocal Co-IP, in vitro DUB assays, BAP1 CTD/ASXM mutagenesis, senescence assays","pmids":["26416890"],"confidence":"High","gaps":["Genome-wide deubiquitination targets not mapped","Structural basis of ASXM-CTD interaction not solved"]},{"year":2015,"claim":"Linking ASXL2 to nuclear-receptor and metabolic biology, it was shown to bind PPARγ and drive osteoclast differentiation and bone resorption through PPARγ/c-Fos and PGC-1β branches, with knockout mice osteopetrotic, lipodystrophic, and insulin resistant.","evidence":"Asxl2 knockout mice, osteoclast differentiation and bone resorption assays, signaling epistasis","pmids":["26051940"],"confidence":"High","gaps":["Chromatin targets downstream of PPARγ/ASXL2 not defined","Direct PPARγ interaction interface not mapped"]},{"year":2015,"claim":"Establishing ASXL2 as an ERα coactivator scaffold, it was shown to bind ligand-bound ERα, read H3K4me2 via its PHD finger, and recruit LSD1/UTX/MLL2 to estrogen-responsive promoters to drive proliferation.","evidence":"Co-IP, ChIP-seq, PHD finger pulldowns, siRNA knockdown, xenograft assays","pmids":["26640146"],"confidence":"High","gaps":["PHD reader specificity not structurally characterized","Interplay with the BAP1 complex at these loci unresolved"]},{"year":2017,"claim":"Two concurrent studies defined ASXL2's role in hematopoiesis, showing it is required for HSC self-renewal and that its loss causes MDS-like disease and promotes AML1-ETO leukemogenesis through altered enhancer accessibility and histone marks.","evidence":"Conditional Asxl2 knockout mice, HSC transplantation and paired-daughter assays, ATAC-seq, H3K27ac/H3K4me1/2 ChIP","pmids":["28516957","28593990"],"confidence":"High","gaps":["Direct biochemical link between ASXL2 and RUNX1/AML1-ETO not established","Whether BAP1/MLL3 axis drives the hematopoietic phenotype unresolved"]},{"year":2020,"claim":"Probing cell-type-specific metabolic function, myeloid ASXL2 deletion was shown to protect against diet-induced obesity by preserving brown fat thermogenesis and catecholamine availability.","evidence":"LysM-Cre Asxl2 conditional KO, HFD metabolic phenotyping, in vivo nanoparticle siRNA, energy expenditure and catecholamine measurements","pmids":["32310225"],"confidence":"High","gaps":["Chromatin targets in macrophages mediating the phenotype not identified","Connection to the BAP1/MLL3 complex untested"]},{"year":2022,"claim":"Resolving how the BAP1 complex couples deubiquitination to active marks, ASXL2 was shown to directly bridge BAP1 to MLL3/COMPASS, an interaction switched off by CARM1 methylation at R639/R641.","evidence":"Co-IP, ChIP-seq, siRNA, site-directed mutagenesis, arginine methylation assays","pmids":["36197977"],"confidence":"High","gaps":["Structural basis of ASXL2-MLL3 contact unresolved","Physiological contexts where CARM1 regulates this switch not defined"]},{"year":2025,"claim":"Extending ASXL2's epigenetic balancing role to stem-cell differentiation, knockdown in periodontal ligament stem cells was shown to shift histone marks toward repression and impair osteogenesis.","evidence":"Lentiviral shRNA in hPDLSCs, ALP/Alizarin Red assays, histone modification western blots, qPCR","pmids":["40680514"],"confidence":"Medium","gaps":["Single lab without independent replication","Direct gene targets and complex partners not defined"]},{"year":2026,"claim":"Connecting ASXL2 to ciliogenesis and male fertility, it was shown to maintain EZH2/H3K27me3-mediated repression of CEP162, the loss of which disrupts axonemal microtubule stability via TUBB3 competition.","evidence":"ASXL2 loss-of-function in spermatogenic cells, ChIP for EZH2/H3K27me3 at CEP162 promoter, protein competition assays, spermatid morphology","pmids":["41782374"],"confidence":"Medium","gaps":["Single lab without independent replication","Direct ASXL2-EZH2 interaction not biochemically shown","In vivo fertility consequence not established"]},{"year":null,"claim":"How ASXL2's two opposing activities — promoting H2A-K119 deubiquitination/H3K4 methylation versus sustaining EZH2-dependent H3K27me3 repression — are selected at a given locus and integrated with nuclear-receptor signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ASXL2 complexes","Rules governing activating-versus-repressive recruitment unknown","No human disease established by direct genetic evidence in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6,13]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,10,12]}],"complexes":["BAP1 complex","MLL3/COMPASS"],"partners":["BAP1","MLL3","CARM1","EZH2","ESR1","PPARG","LXRA","WTIP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q76L83","full_name":"Putative Polycomb group protein ASXL2","aliases":["Additional sex combs-like protein 2"],"length_aa":1435,"mass_kda":153.8,"function":"Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility (By similarity). Involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as peroxisome proliferator-activated receptor gamma (PPARG). Acts as coactivator for PPARG and enhances its adipocyte differentiation-inducing activity; the function seems to involve differential recruitment of acetylated and methylated histone H3. Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1) (PubMed:30664650, PubMed:36180891). The PR-DUB complex is an epigenetic regulator of gene expression and acts as a transcriptional coactivator, affecting genes involved in development, cell communication, signaling, cell proliferation and cell viability (PubMed:30664650, PubMed:36180891). ASXL1, ASXL2 and ASXL3 function redundantly in the PR-DUB complex (By similarity) (PubMed:30664650). The ASXL proteins are essential for chromatin recruitment and transcriptional activation of associated genes (By similarity). ASXL1 and ASXL2 are important for BAP1 protein stability (PubMed:30664650)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q76L83/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASXL2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":77,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ASXL2","total_profiled":1310},"omim":[{"mim_id":"617190","title":"SHASHI-PENA SYNDROME; SHAPNS","url":"https://www.omim.org/entry/617190"},{"mim_id":"615115","title":"ASXL TRANSCRIPTIONAL REGULATOR 3; ASXL3","url":"https://www.omim.org/entry/615115"},{"mim_id":"612991","title":"ASXL TRANSCRIPTIONAL REGULATOR 2; ASXL2","url":"https://www.omim.org/entry/612991"},{"mim_id":"612990","title":"ASXL TRANSCRIPTIONAL REGULATOR 1; ASXL1","url":"https://www.omim.org/entry/612990"},{"mim_id":"603089","title":"BRCA1-ASSOCIATED PROTEIN 1; BAP1","url":"https://www.omim.org/entry/603089"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ASXL2"},"hgnc":{"alias_symbol":["ASXH2","FLJ10898","KIAA1685"],"prev_symbol":[]},"alphafold":{"accession":"Q76L83","domains":[{"cath_id":"-","chopping":"269-369","consensus_level":"medium","plddt":82.2413,"start":269,"end":369},{"cath_id":"-","chopping":"1407-1435","consensus_level":"medium","plddt":64.3214,"start":1407,"end":1435},{"cath_id":"1.10.10","chopping":"11-87","consensus_level":"medium","plddt":76.1365,"start":11,"end":87}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q76L83","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q76L83-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q76L83-F1-predicted_aligned_error_v6.png","plddt_mean":46.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASXL2","jax_strain_url":"https://www.jax.org/strain/search?query=ASXL2"},"sequence":{"accession":"Q76L83","fasta_url":"https://rest.uniprot.org/uniprotkb/Q76L83.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q76L83/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q76L83"}},"corpus_meta":[{"pmid":"26416890","id":"PMC_26416890","title":"The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26416890","citation_count":115,"is_preprint":false},{"pmid":"21490954","id":"PMC_21490954","title":"Mouse genome-wide association and systems genetics identify Asxl2 as a regulator of bone mineral density and osteoclastogenesis.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21490954","citation_count":97,"is_preprint":false},{"pmid":"24973361","id":"PMC_24973361","title":"Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations.","date":"2014","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/24973361","citation_count":94,"is_preprint":false},{"pmid":"12888926","id":"PMC_12888926","title":"Identification and characterization of ASXL2 gene in silico.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12888926","citation_count":90,"is_preprint":false},{"pmid":"26051940","id":"PMC_26051940","title":"ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26051940","citation_count":63,"is_preprint":false},{"pmid":"19270745","id":"PMC_19270745","title":"Functional conservation of Asxl2, a murine homolog for the Drosophila enhancer of trithorax and polycomb group gene Asx.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19270745","citation_count":60,"is_preprint":false},{"pmid":"28516957","id":"PMC_28516957","title":"ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28516957","citation_count":58,"is_preprint":false},{"pmid":"25835095","id":"PMC_25835095","title":"Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine.","date":"2015","source":"Expert review of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25835095","citation_count":52,"is_preprint":false},{"pmid":"26640146","id":"PMC_26640146","title":"ASXL2 promotes proliferation of breast cancer cells by linking ERα to histone methylation.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26640146","citation_count":44,"is_preprint":false},{"pmid":"28593990","id":"PMC_28593990","title":"Loss of Asxl2 leads to myeloid malignancies in mice.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28593990","citation_count":27,"is_preprint":false},{"pmid":"23046516","id":"PMC_23046516","title":"Maintenance of adult cardiac function requires the chromatin factor Asxl2.","date":"2012","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/23046516","citation_count":25,"is_preprint":false},{"pmid":"30251205","id":"PMC_30251205","title":"Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study.","date":"2018","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/30251205","citation_count":24,"is_preprint":false},{"pmid":"36197977","id":"PMC_36197977","title":"CARM1-mediated methylation of ASXL2 impairs tumor-suppressive function of MLL3/COMPASS.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36197977","citation_count":16,"is_preprint":false},{"pmid":"32310225","id":"PMC_32310225","title":"Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure.","date":"2020","source":"The Journal of clinical 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BAP1 is essential for maintaining ASXL2 (but not ASXL1) protein stability, and cancer-associated loss of BAP1 results in ASXL2 destabilization.\",\n      \"method\": \"Co-immunoprecipitation, in vitro DUB activity assays, mutagenesis of BAP1 CTD and ASXM domains, cell proliferation and senescence assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, in vitro enzymatic assays, domain mutagenesis, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"26416890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cancer-associated mutations in ASXL2 disrupt BAP1 DUB activity, and BAP1 interaction with ASXL2 regulates cell senescence, implicating the BAP1/ASXL2 axis in tumor suppression.\",\n      \"method\": \"Mutagenesis of ASXL2 cancer-associated variants, DUB activity assays, cell senescence assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assays plus cellular functional readouts with defined mutations, multiple orthogonal methods\",\n      \"pmids\": [\"26416890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ASXL2, as a subunit of the BAP1 complex, mediates a direct interaction with MLL3/COMPASS, and ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. PRMT4/CARM1 methylates ASXL2 at R639/R641, blocking its binding to MLL3 and impairing MLL3/COMPASS-dependent gene expression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, siRNA knockdown, site-directed mutagenesis, arginine methylation assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct interaction confirmed by Co-IP, PTM writer identified by methylation assay, functional consequence assessed by ChIP-seq and gene expression, multiple orthogonal methods\",\n      \"pmids\": [\"36197977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASXL2 interacts with PPARγ and regulates osteoclast formation via a PPARγ/c-Fos-dependent pathway; ASXL2 is also required for RANK ligand- and thiazolidinedione-induced bone resorption independently of PGC-1β, and promotes osteoclast mitochondrial biogenesis in a PGC-1β-dependent but c-Fos-independent manner. ASXL2-/- mice are insulin resistant, lipodystrophic, and severely osteopetrotic due to failed osteoclast differentiation.\",\n      \"method\": \"Asxl2 knockout mice, osteoclast differentiation assays, bone resorption assays, signaling pathway epistasis experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotypes and multiple pathway epistasis experiments across independent signaling branches\",\n      \"pmids\": [\"26051940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASXL2 interacts with ligand-bound ERα and mediates ERα transcriptional activation. ASXL2 forms a complex with histone methylation modifiers LSD1, UTX, and MLL2, which are recruited to E2-responsive gene promoters via ASXL2, regulating methylations at H3K4, H3K9, and H3K27. The PHD finger of ASXL2 preferentially binds dimethylated H3K4, which is required for ERα activation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, pulldown assays with PHD finger, siRNA knockdown, xenograft tumor assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, PHD finger binding assay, and in vivo xenograft validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26640146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss of Asxl2 in mice reduces trimethylation of histone H3 lysine 27 (H3K27me3) in the heart, demonstrating that Asxl2 promotes PcG-associated histone modification. Asxl2 mutant mice display both posterior and anterior transformations of the axial skeleton, indicating dual roles in PcG and trxG activity. Asxl2-/- mice develop enlarged hearts with impaired ventricular function.\",\n      \"method\": \"Gene-trap knockout mouse, histone modification analysis (western blot for H3K27me3), skeletal phenotyping, histological analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with direct histone modification measurement and defined skeletal/cardiac phenotypic readouts; replicated by subsequent cardiac study\",\n      \"pmids\": [\"19270745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Asxl2 is required for maintenance of ventricular function and for repression of β-MHC in adult mouse hearts. Asxl2 and the histone methyltransferase Ezh2 co-localize to the β-MHC promoter, indicating Asxl2 directly represses β-MHC through Ezh2-mediated chromatin modification. Loss of Asxl2 causes progressive deterioration of ventricular function (~37% reduction in fractional shortening by 10 months).\",\n      \"method\": \"Asxl2-/- mice echocardiography, ChIP showing Asxl2 and Ezh2 co-occupancy at β-MHC promoter, cardiac gene expression analysis\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cardiac functional phenotype, ChIP showing direct promoter co-occupancy with Ezh2, multiple methods in single lab\",\n      \"pmids\": [\"23046516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Asxl2 regulates bone mineral density and osteoclastogenesis; knockdown of Asxl2 in bone marrow macrophages impairs their ability to form osteoclasts. Asxl2 knockout mice have reduced BMD.\",\n      \"method\": \"GWAS/systems genetics in HMDP, Asxl2 knockout mice (BMD phenotyping), siRNA knockdown in bone marrow macrophages with osteoclast differentiation assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO phenotype plus siRNA knockdown in primary cells with defined osteoclastogenesis readout, replicated in subsequent independent study\",\n      \"pmids\": [\"21490954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ASXL2 is required for normal haematopoietic stem cell self-renewal; Asxl2 loss promotes AML1-ETO-driven leukemogenesis. ASXL2 target genes strongly overlap with those of RUNX1 and AML1-ETO, and ASXL2 loss is associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci.\",\n      \"method\": \"Asxl2 conditional knockout mice, hematopoietic stem cell transplantation assays, ATAC-seq for chromatin accessibility, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with HSC functional assays, ATAC-seq chromatin analysis, and leukemogenesis model; multiple orthogonal methods\",\n      \"pmids\": [\"28516957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deletion of Asxl2 in mice leads to MDS-like disease with expanded long-term HSCs and granulocyte-macrophage progenitors. Asxl2 loss enhances HSC self-renewal (paired daughter cell assays) and alters H3K27ac and H3K4me1/2 at loci critical for HSC self-renewal, differentiation, and apoptosis.\",\n      \"method\": \"Asxl2 knockout mice, bone marrow transplantation, paired daughter cell assays, histone modification ChIP analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with clonal HSC functional assays and direct histone modification measurements; independent replication of HSC phenotype across two concurrent studies\",\n      \"pmids\": [\"28593990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ASXL2 activates LXRα transcriptional activity through direct interaction with LXRα in the presence of ligand, while ASXL1 suppresses it; knockdown of ASXL2 decreases lipid accumulation in H4IIE cells. ChIP assays show ligand-dependent recruitment of ASXL2 to ABCA1 promoters.\",\n      \"method\": \"Transcriptional reporter assays, Co-immunoprecipitation, ChIP assay, siRNA knockdown with lipid accumulation readout\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct interaction by Co-IP, ChIP confirmation of promoter recruitment, functional knockdown, single lab\",\n      \"pmids\": [\"24321552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ASXL2 directly interacts with the LIM domain-containing protein WTIP; WTIP represses ASXL2-stimulated retinoic acid-dependent transcription, blocking ASXL2's stimulatory effect. Both proteins are expressed in mouse embryonic epicardial cells.\",\n      \"method\": \"Genetic and biochemical interaction assays, luciferase reporter assays in HeLa cells, co-expression analysis in mouse embryonic epicardium\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct interaction confirmed biochemically and genetically, functional reporter assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"25065743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Myeloid-specific deletion of Asxl2 confers resistance to diet-induced obesity by protecting energy expenditure and brown adipose tissue metabolism, associated with suppressed macrophage inflammatory cytokine expression and relatively increased catecholamines (due to suppressed catecholamine degradation by macrophages). Nanoparticle-based siRNA suppression of macrophage Asxl2 prevented HFD-induced obesity.\",\n      \"method\": \"Myeloid-specific Asxl2 conditional KO (LysM-Cre), high-fat diet metabolic phenotyping, nanoparticle siRNA delivery in vivo, energy expenditure measurements, cytokine/catecholamine measurements\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined metabolic phenotype plus orthogonal siRNA rescue experiment and mechanistic measurement of catecholamine pathway\",\n      \"pmids\": [\"32310225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ASXL2 promotes EZH2 binding to the CEP162 promoter region (3482–3511 bp), maintaining H3K27me3 and repressing CEP162 transcription. Hypoxia-induced downregulation of ASXL2 reduces EZH2 occupancy, increases CEP162 expression, and CEP162 then competes with TUBA3A for TUBB3 binding, depleting ciliary TUBB3 and destabilizing axonemal microtubules, causing spermatid maturation defects.\",\n      \"method\": \"ASXL2 loss-of-function in spermatogenic cells, ChIP for EZH2/H3K27me3 at CEP162 promoter, protein binding/competition assays (TUBB3/CEP162/TUBA3A), spermatid morphology analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and protein interaction assays establish mechanism, but single lab and single publication with no independent replication\",\n      \"pmids\": [\"41782374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ASXL2 knockdown in human periodontal ligament stem cells (hPDLSCs) impairs osteogenic differentiation, suppresses H3K4me3 (activating mark), and increases H2AK119ub and H3K27me3 (repressive marks) at osteogenic gene loci, demonstrating that ASXL2 modulates osteogenic competency through histone modification balance.\",\n      \"method\": \"Lentiviral shRNA knockdown in hPDLSCs, ALP activity assay, Alizarin Red mineralization, western blot for H3K4me3/H2AK119ub/H3K27me3, qPCR for osteogenic markers\",\n      \"journal\": \"International dental journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — loss-of-function with direct histone modification readouts, but single lab and single publication with no independent replication\",\n      \"pmids\": [\"40680514\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASXL2 is an epigenetic scaffold protein that forms a mutually exclusive complex with the deubiquitinase BAP1 (through ASXM domain–CTD interaction), stimulating H2A-K119 deubiquitination; it also bridges BAP1 to the MLL3/COMPASS H3K4 methyltransferase complex (interaction negatively regulated by CARM1-mediated methylation at R639/R641), co-occupies target promoters/enhancers with EZH2 to maintain H3K27me3-dependent gene repression, interacts with nuclear receptors PPARγ, LXRα, and ERα to regulate lipid/glucose metabolism and breast cancer cell proliferation, and is required for normal haematopoietic stem cell self-renewal and osteoclastogenesis, with its loss causing MDS-like disease, osteopetrosis, and cardiac dysfunction in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ASXL2 is an epigenetic scaffold protein that couples histone-modifying machineries to chromatin to control gene expression programs governing hematopoiesis, bone remodeling, cardiac function, and metabolism [#0, #5, #7]. It forms a mutually exclusive complex with the deubiquitinase BAP1, engaging the BAP1 C-terminal domain through its ASXM domain to enable ubiquitin binding and H2A-K119 deubiquitination; BAP1 in turn stabilizes ASXL2 protein, and cancer-associated ASXL2 mutations disrupt BAP1 DUB activity, linking this axis to senescence control and tumor suppression [#0, #1]. Within the BAP1 complex, ASXL2 bridges to the MLL3/COMPASS H3K4 methyltransferase to sustain enhancer occupancy and target-gene expression, an interaction blocked by CARM1/PRMT4-mediated methylation of ASXL2 at R639/R641 [#2]. ASXL2 also acts as a repressive cofactor, co-occupying target promoters with EZH2 to maintain H3K27me3-dependent silencing of genes such as cardiac \\u03b2-MHC [#5, #6], while its PHD finger reads dimethylated H3K4 and recruits LSD1, UTX, and MLL2 to mediate ligand-dependent transcriptional activation by ER\\u03b1 and the nuclear receptors PPAR\\u03b3 and LXR\\u03b1, integrating epigenetic control of lipid and glucose metabolism [#3, #4, #10]. Functionally, ASXL2 is required for normal hematopoietic stem cell self-renewal, and its loss causes MDS-like disease and promotes AML1-ETO-driven leukemogenesis through altered enhancer accessibility and histone marks [#8, #9], drives osteoclastogenesis and bone mineral density [#3, #7], and maintains adult ventricular function [#5, #6]. Beyond these characterized roles, no further mechanistic detail has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing whether ASXL2 functions in chromatin regulation in vivo, this work showed it promotes Polycomb-associated H3K27me3 and governs body-axis patterning and heart development.\",\n      \"evidence\": \"Gene-trap Asxl2 knockout mice with H3K27me3 western blots, skeletal and cardiac phenotyping\",\n      \"pmids\": [\"19270745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular partners mediating H3K27me3 changes not identified\", \"Dual PcG/trxG activity not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Addressing the cellular basis of skeletal phenotypes, ASXL2 was shown to be cell-autonomously required for osteoclast formation and bone mineral density.\",\n      \"evidence\": \"Systems genetics (HMDP), Asxl2 knockout mice BMD phenotyping, siRNA knockdown in bone marrow macrophages with osteoclast differentiation assays\",\n      \"pmids\": [\"21490954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target genes in osteoclast lineage not defined\", \"Chromatin mechanism in osteoclastogenesis unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"To pinpoint how ASXL2 controls cardiac gene expression, this study showed it co-occupies the \\u03b2-MHC promoter with EZH2 to maintain repression and ventricular function.\",\n      \"evidence\": \"Asxl2-/- echocardiography and ChIP for Asxl2/Ezh2 co-occupancy at the \\u03b2-MHC promoter\",\n      \"pmids\": [\"23046516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between ASXL2 and EZH2 not demonstrated biochemically\", \"Genome-wide co-occupancy not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Testing whether ASXL family members differentially regulate nuclear receptors, ASXL2 was found to activate LXR\\u03b1 transcription in a ligand-dependent manner, opposite to ASXL1.\",\n      \"evidence\": \"Reporter assays, Co-IP, ChIP at ABCA1 promoter, siRNA knockdown with lipid accumulation readout\",\n      \"pmids\": [\"24321552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Histone-modifying machinery recruited to LXR\\u03b1 targets not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying a negative regulator of ASXL2 cofactor activity, WTIP was shown to directly bind ASXL2 and repress its retinoic-acid-dependent transcriptional stimulation.\",\n      \"evidence\": \"Biochemical/genetic interaction assays and luciferase reporters in HeLa cells, epicardial co-expression\",\n      \"pmids\": [\"25065743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Physiological context of WTIP-ASXL2 regulation in vivo unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining the core biochemical complex, ASXL2 was shown to form a BAP1-specific (mutually exclusive with ASXL1) complex via ASXM\\u2013CTD contact required for H2A-K119 deubiquitination, with BAP1 reciprocally stabilizing ASXL2 and cancer mutations disrupting DUB activity.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro DUB assays, BAP1 CTD/ASXM mutagenesis, senescence assays\",\n      \"pmids\": [\"26416890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide deubiquitination targets not mapped\", \"Structural basis of ASXM-CTD interaction not solved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking ASXL2 to nuclear-receptor and metabolic biology, it was shown to bind PPAR\\u03b3 and drive osteoclast differentiation and bone resorption through PPAR\\u03b3/c-Fos and PGC-1\\u03b2 branches, with knockout mice osteopetrotic, lipodystrophic, and insulin resistant.\",\n      \"evidence\": \"Asxl2 knockout mice, osteoclast differentiation and bone resorption assays, signaling epistasis\",\n      \"pmids\": [\"26051940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin targets downstream of PPAR\\u03b3/ASXL2 not defined\", \"Direct PPAR\\u03b3 interaction interface not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing ASXL2 as an ER\\u03b1 coactivator scaffold, it was shown to bind ligand-bound ER\\u03b1, read H3K4me2 via its PHD finger, and recruit LSD1/UTX/MLL2 to estrogen-responsive promoters to drive proliferation.\",\n      \"evidence\": \"Co-IP, ChIP-seq, PHD finger pulldowns, siRNA knockdown, xenograft assays\",\n      \"pmids\": [\"26640146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PHD reader specificity not structurally characterized\", \"Interplay with the BAP1 complex at these loci unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two concurrent studies defined ASXL2's role in hematopoiesis, showing it is required for HSC self-renewal and that its loss causes MDS-like disease and promotes AML1-ETO leukemogenesis through altered enhancer accessibility and histone marks.\",\n      \"evidence\": \"Conditional Asxl2 knockout mice, HSC transplantation and paired-daughter assays, ATAC-seq, H3K27ac/H3K4me1/2 ChIP\",\n      \"pmids\": [\"28516957\", \"28593990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between ASXL2 and RUNX1/AML1-ETO not established\", \"Whether BAP1/MLL3 axis drives the hematopoietic phenotype unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Probing cell-type-specific metabolic function, myeloid ASXL2 deletion was shown to protect against diet-induced obesity by preserving brown fat thermogenesis and catecholamine availability.\",\n      \"evidence\": \"LysM-Cre Asxl2 conditional KO, HFD metabolic phenotyping, in vivo nanoparticle siRNA, energy expenditure and catecholamine measurements\",\n      \"pmids\": [\"32310225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin targets in macrophages mediating the phenotype not identified\", \"Connection to the BAP1/MLL3 complex untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolving how the BAP1 complex couples deubiquitination to active marks, ASXL2 was shown to directly bridge BAP1 to MLL3/COMPASS, an interaction switched off by CARM1 methylation at R639/R641.\",\n      \"evidence\": \"Co-IP, ChIP-seq, siRNA, site-directed mutagenesis, arginine methylation assays\",\n      \"pmids\": [\"36197977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ASXL2-MLL3 contact unresolved\", \"Physiological contexts where CARM1 regulates this switch not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending ASXL2's epigenetic balancing role to stem-cell differentiation, knockdown in periodontal ligament stem cells was shown to shift histone marks toward repression and impair osteogenesis.\",\n      \"evidence\": \"Lentiviral shRNA in hPDLSCs, ALP/Alizarin Red assays, histone modification western blots, qPCR\",\n      \"pmids\": [\"40680514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Direct gene targets and complex partners not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connecting ASXL2 to ciliogenesis and male fertility, it was shown to maintain EZH2/H3K27me3-mediated repression of CEP162, the loss of which disrupts axonemal microtubule stability via TUBB3 competition.\",\n      \"evidence\": \"ASXL2 loss-of-function in spermatogenic cells, ChIP for EZH2/H3K27me3 at CEP162 promoter, protein competition assays, spermatid morphology\",\n      \"pmids\": [\"41782374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Direct ASXL2-EZH2 interaction not biochemically shown\", \"In vivo fertility consequence not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ASXL2's two opposing activities — promoting H2A-K119 deubiquitination/H3K4 methylation versus sustaining EZH2-dependent H3K27me3 repression — are selected at a given locus and integrated with nuclear-receptor signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ASXL2 complexes\", \"Rules governing activating-versus-repressive recruitment unknown\", \"No human disease established by direct genetic evidence in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 10, 12]}\n    ],\n    \"complexes\": [\n      \"BAP1 complex\",\n      \"MLL3/COMPASS\"\n    ],\n    \"partners\": [\n      \"BAP1\",\n      \"MLL3\",\n      \"CARM1\",\n      \"EZH2\",\n      \"ESR1\",\n      \"PPARG\",\n      \"LXRA\",\n      \"WTIP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}